Tumor necrosis factor-α (TNF-α) is a pleiotropic cytokine, and is produced by activated macrophages/monocytes and lymphocytes. TNF-α is a potent mediator in inflammatory and immune responses, including the recruitment of leukocytes to injured tissues during bacterial and other microbial infections, and following stimulation with inflammatory substances. When present in excessive quantities, however, TNF-α is known to cause tissue injury, and has been implicated in the pathology associated with several inflammatory and autoimmune diseases.
The biological effects of TNF are mediated through two distinct receptors, TNF-RI and TNF-RII (in humans, p55 and p75, respectively), which differ in sequence and molecular mass. TNF-RI is reported to he present at low levels in most, if not all, human cell types, and expression of the gene in humans can be upregulated by infection, interferons, and modulators of second messengers, such as phorbol esters. The extracellular portions of both receptors also exist in soluble forms, which are derived by proteolytic cleavage from the cell surface. The soluble TNF receptors retain the ability to bind TNF in solution. Activated cells often shed their TNF receptors, which can render the target cell less sensitive to the biological effects of TNF. Soluble TNF receptors have been identified in urine and sera from healthy individuals, and have been shown to be elevated in some chronic diseases and following inoculation with agents that induce TNF-α release.